The present invention relates to the use of a liposomal preparation for the manufacture of a pharmaceutical composition and the use of such a composition for the treatment of “triple receptor negative” breast cancer.
Today the systemic treatment of breast cancer offers three major different treatment modalities and the applicability of these different treatment options is substantially dependent on the receptor status of the patient (Bernard-Marty et al., 2004). Endocrine and biological therapy requires the presence of the respective receptors on the cancer cells, whereas cytotoxic chemotherapy is independent of those specified receptors.
In patients with hormone-receptor-positive breast cancer, endocrine therapy or a combination thereof is usually the treatment of choice (Bernard-Marty et al., 2004; Gradishar, 2004). In the presence of estrogen receptor (ER) and/or progesterone receptor (PgR) response rates of greater than 80% have been observed. In general, postmenopausal patients exhibit higher ER and PgR expression than their premenopausal counterparts.
The gold standard in endocrine therapy has been the selective ER modulator tamoxifen. It inhibits binding of estrogen to the estrogen receptor, thereby disrupting a series of cellular mechanisms that regulate cellular replication. Despite being tolerated well in most cases, tamoxifen is associated to a number of adverse events. Although the drug has a high overall response rate, disease relapse and resistance develop in many patients. The resistance might be related to an altered interaction between tamoxifen and the estrogen receptor.
To overcome resistance, alternative endocrine therapies have been developed that challenge the role of tamoxifen (Bernard-Marty et al., 2004) (Gradishar, 2004). Aromatase inhibitors directly interfere with the biosynthesis of estrogen by inhibiting the enzyme aromatase which converts androstenedione into estradiol. The latest generation of these inhibitors comprises nonsteroidal drugs like letrozol, anastrozol and vostrozol and steroidal drugs like exemestane. The favourable safety and response rates for this class of medicaments has established aromatase inhibitors as the standard endocrine therapy for the treatment of metastatic breast cancer in postmenopasal women.
The antiestrogen fulvestrant circumvents resistance issues related to tamoxifen by a different mechanism of action. It binds the ER, thereby inhibiting DNA binding and decreases the ER concentration by promoting the degradation of the ER.
In pre-menopausal ER and PgR positive women, endocrine therapies beside tamoxifen include ovarian ablation by surgery or radiotherapy and luteinizing hormone releasing hormone (LHRH) analogues (Bernard-Marty et al., 2004). In these patients, the ovaries are the major source of estrogen synthesis and ovarian ablation was the original therapy for breast cancer. To avoid the adverse events of ovaraian ablation by surgery or irradiation, the ovarian function can be suppressed by LHRH analogues. LHRH analogue like goserelin, leuprolide and triptorelin suppress the ovarian estrogen production by down regulation of pituitary release of gonadotropins through their antagonistic action on the GnRH (gonadotropins-releasing hormone) receptors (Prowell and Davidson, 2004).
With growing understanding and intense research in the biology of breast cancer, several new defined targets for antitumour therapy have emerged in the last years. Among those, HER-2/neu has been established as a main target for therapy. The human endothelial growth factor receptor 2 (HER-2) is amplified and/or overexpressed in approximately 30% of breast cancer tumours (Slamon et al., 1987) and is targeted by the inhibitory antibody trastuzumab. As trastuzumab is one of the few agents that led to an improvement in the overall survival in metastatic breast cancer, HER-2 status evaluation became indispensable for optimal treatment (Bernard-Marty et al., 2004).
Trastuzumab is approved for the second line treatment of metastatic breast cancer for HER-2 positive patients who have received one or more regimes of chemotherapy or for the first line treatment in combination with paclitaxel. Trastuzumab is commonly used until disease progression. It is generally well tolerated with congestive heart failure being the most important side effect. The use of trastuzumab is constantly evaluated in different mono and combination therapies with differing patient populations and dosing schedules.
The receptor status for ER, PgR and HER-2 can be determined by standard immunohistochemical or enzyme based assays (IHC) assays (Chebil et al., 2003; Yamashita et al., 2006) (Schaller et al., 2001). HER-2 status can also be assessed by the detection of gene amplification by fluorescence in situ hybridization (FISH) (Kallioniemi et al., 1992).
Overall, therapies depending on the receptor status of the patient have proven great benefit for the treatment of breast cancer.
Unfortunately about 15% of all breast cancer cases are negative for ER, PgR and HER-2. In these cases prognosis is very poor with an 80% relapse rate and a median survival of only 6 months.
For ER, PgR and HER-2 negative patients, as well as for patients with endocrine therapy resistant disease, chemotherapy is the only therapeutic option. Frequently applied chemotherapeutic drugs in breast cancer are drugs from the anthracycline class, the taxane class and to a lower extent antimetabolites, e.g. capecitabine, gemcitabine, alkylating agents and vinca alkaloids. These drugs are used in two basic applications schemes. The drugs can be applied as single agents in a sequential fashion or they can be used in a combination regime. Of course the two treatment modalities can be combined to some extent.
The anthracyclines, and especially doxorubicine and epirubicine, have been shown to be active agents in the treatment of breast cancer and anthracycline-containing combination regimes are common first line treatments in patients who have not received anthracyclines in an adjuvant setting. Common combination treatment consists for example of doxorubicine/epirubicine plus cyclophospamide, doxorubicin/epirubicin plus cyclophosphamide and 5-fluorouracil, or combinations of anthracyclines and capecitabine or gemcitabine (O'Shaughnessy, 2005).
With the common use of anthracyclines in early stages of breast cancer treatment, the likelihood of anthracycline resistant forms of breast cancer, however, increases (Bernard-Marty et al., 2004).
The introduction of the taxanes paclitaxel and docetaxel into the treatment further improved the management of the disease in first and second line treatment. Paclitaxel has a unique mechanism of action and a broad spectrum of antiproliferative activity because paclitaxel binds to microtubules, promotes tubulin polymerisation and stabilizes the assembled microtubules. As a result, paclitaxel blocks the cell cycle at prophase resulting in an accumulation of cells in the G2/M phase.
Unfortunately, paclitaxel has extreme low solubility in water, which makes it difficult to provide a suitable dosage form. Currently, paclitaxel is formulated and administered in a vehicle containing Cremophor EL (a polyethoxylated castor oil) and ethanol in a 50:50 (vol/vol) ratio. This solution is diluted 1:10 in saline before being administered to humans. However, various severe side reactions, such as hypersensitivity and hypertensive reactions, nephrotoxicity and neurotoxicity, for example, have been reported in patients due to Cremophor EL formulation.
U.S. Pat. No. 5,648,090, U.S. Pat. No. 5,424,073 and U.S. Pat. No. 6,146,659 (Rahman et al.) provide a liposomal encapsulated paclitaxel for a method for treating cancer in mammals. These patents disclose a method of administering to the host a pharmaceutical composition of a therapeutically effective amount of liposomes which include a liposome forming material, cardiolipin, and an agent such as paclitaxel, or an antineoplastic derivative of paclitaxel, or a mixture thereof, with a pharmaceutically acceptable excipient.
From U.S. Pat. No. 5,837,283 it has been known that cationic liposomes preferentially target the angiogenic endothelial cells in solid tumours. From the disclosure of WO 2005/0309533 (Teifel et al.) it is known that a treatment with paclitaxel encapsulated in cationic liposomes might proof beneficial in various cancer indications. The document discloses the application of cationic liposomal paclitaxel formulations to humans suffering from melanoma, prostate, pancreatic, gastro-intestinal, colorectal, and breast cancer. The application also describes the use of cationic liposomal paclitaxel formulations in different animal models of pancreatic cancer, uterus sarcoma, colon carcinoma and head and neck squamous-cell carcinoma.
Liposomal formulations are also known for anthraycline drugs. Doxorubicine has been encapsulated in uncharged pegylated or unpegylated liposomes for the treatment of breast cancer. These formulations have been used for the treatment of breast cancer in a first line (Chan et al., 2004) and in a second line (Keller et al., 2004) regime.
In summary most of today's therapeutical options in breast cancer are dependent on the receptor status of the patients. Particularly patients of the triple receptor negative subgroup are not eligible to the highly effective endocrine therapies. The options for chemotherapeutical treatment are limited and a resistance against the existing regimes like the anthracyclines is frequently observed. Consequently there is a high unmet medical need for the development of new therapies in this indication.
Thus, it was the underlying problem of the present invention to provide an improvement in the treatment of triple receptor negative breast cancer, especially for patients who have become refractory to anthracycline treatment.